Comparative effects of theophylline and isosorbide dinitrate on exercise capacity in stable angina pectoris, and their mechanisms of action

Abstract

While the role of nitrates in the prevention and treatment of myocardial ischemia is well established, the use of theophylline, proposed almost a century ago, is still controversial. Also controversial is its mechanism of action, initially thought to be coronary dilation. In this randomized, singleblind study, the acute effects on exercise capacity of sublingual isosorbide dinitrate (10 mg) and of intravenous theophylline ethylenediamine (7 mg/kg) were assessed in 10 patients with chronic stable angina and positive exercise test. After the administration of theophylline, the time to onset of angina, the heart rate-blood pressure product at 1-mm ST-segment depression and the exercise duration were similar to that after isosorbide dinitrate administration (9.8 ± 2.3 vs 9.3 ± 1.7 minutes, 207 ± 41 vs 207 ± 48 beats/min · mm Hg · 10 −2 and 10.8 ± 2 vs 10.4 ± 2 minutes, respectively). Both drugs significantly (p < 0.001) improved all these parameters compared to the baseline exercise test. The effect of the 2 drugs on the diameters of angiographically normal segments of large epicardial coronary arteries was then assessed using computerized quantitative angiography in 10 other patients with stable angina. Whereas theophylline failed to increase the coronary diameters compared to that in the baseline angiogram (2.9 ± 0.6 vs 2.9 ± 0.6 mm, respectively), the subsequent administration of isosorbide dinitrate resulted in an increase up to 3.2 ± 0.7 mm (p < 0.02). Thus, in patients with stable angina, theophylline delays the onset of angina, increases the ischemic threshold and prolongs the exercise duration to the same degree as isosorbide dinitrate. The mechanism of action of these 2 drugs, however, appears to be substantially different. Indeed, while nitrates dilate epicardial coronary arteries and are known to decrease the preload, theophylline does not dilate epicardial coronary arteries and is known to increase the cardiac work. Therefore, a new mechanism of action, probably redistribution of coronary blood flow from nonischemic to ischemic myocardium, should be postulated to explain the antianginal effect of theophylline. This potentially novel antiischemic effect, if confirmed, could open the way to a new class of antianginal drugs.